The determination of the solubility of a chemical compound is a routine requirement in analytical chemistry laboratories. Such determination is for example, commonly required in the development and assessment of new pharmaceutical and agrochemical compounds, many of which contain one or more acidic or basic groups that react with hydrogen ions in aqueous solution.
Traditional methods of determining solubility rely on the addition of a known mass of chemical compound to a known volume of distilled water at a defined pH. The resulting solution is agitated (e.g. by stirring) until an equilibrium state is obtained. Samples of the equilibrated solution are then removed and the solubility determined by known analytical methods. A problem with such traditional methods is that it is not unusual for an extended period of time, sometimes in excess of 48 hours, to be required for an equilibrium state to be reached. Thus, the process is undesirably slow. In addition, over such an extended time period it is not uncommon for environmental factors to affect the test solution. For example, atmospheric carbon dioxide may dissolve in the solution to produce carbonic acid, thereby potentially affecting the pH thereof. Alternatively, the chemical compound itself may be subject to environmental degradation (e.g. as a result of oxidation by atmospheric oxygen).
Overall, it is therefore desirable both from an efficiency and accuracy standpoint to provide a method for more rapid determination of solubility.
A pH-metric method of determining solubility has been described in the literature: ‘pH-metric Solubility. 1. Solubility-pH Profile from Bjerrum Plots. Gibbs Buffer and pKa in the Solid State: Pharm Pharmacol Commun 1998, 4: pages 165-178; and ‘pH-metric Solubility. 2. Correlation Between the Acid-Base Titration and the Saturation Shake-Flask Solubility-pH Methods: Pharmaceutical Research, 2000, 17: pages 85-89. In practice, however this method still typically requires from six to eight hours to conduct and therefore represents only a partial advance over the traditional methods.
The Applicant has now developed a method of determining the solubility of chemical compounds containing one or more acidic or basic groups that is much faster than both traditional and pH-metric methods. A typical solubility determination can be conducted in less than an hour (e.g. 30 to 60 minutes), thereby providing significant process efficiency benefits and reducing the likelihood of environmental factors having any affect on the result. The method may be used for even poorly soluble chemical compounds and is readily susceptible to automation. Additionally, the method of the present invention does not necessarily require the use of co-solvents as are commonly used in more traditional methods, particularly when assessing compounds of low solubility.
Traditional methods of determining solubility are for example, described in the following literature references: The article ‘Physiochemical Properties of Prostaglandin F2α (Tromethamine Salt): Solubility Behavior, Surface Properties, and Ionization Constants: Journal of Pharmaceutical Sciences, 1973, 62: pages 1680-5 describes a method of solubility determination of the subject prostaglandin drug that requires 48 hours for equilibrium to be reached and in which, environmental degradation of the drug over 48 hours is noted at pH≦3. The article ‘General treatment of pH solubility profiles of weak acids and bases. II. Evaluation of thermodynamic parameters from the temperature dependence of solubility profiles applied to a zwitterionic compound: International Journal of Pharmaceutics, 1985, 25: pages 135-145 describes a method of solubility determination that requires 3-5 days for an equilibrium state to be reached.
It is an object of the present invention to provide a method of determining the solubility of chemical compounds containing one or more acidic or basic groups that is more efficient than known methods.
It is an object of the present invention to provide a method of determining the solubility of pharmaceutical or agrochemical chemical compounds containing one or more acidic or basic groups that is more rapid than known methods.